The pathology of HIV-1 is a complex, multistaged phenomenon. We now have a clear view, however, that the asymptomatic phase of most adult infections is characterized by persistent, active virus replication which defines a state of equilibrium between lymphocyte destruction and replenishment. Progression to AIDS is linked to the perturbation of this balance, whereby destruction exceeds the regenerative capacity of the immune system. This proposal addresses the central mechanisms of T lymphocyte development in the human thymus and the impact of HIV- l on this process. Although the role of the thymus in maintenance of the adult immune system is unclear, there is no question of the essential importance of this organ in the generation of fetal and neonatal immunity. Accordingly, our studies focus on the consequences of HIV-1 infection within the developing immune system. Numerous studies have demonstrated that thymocytes are highly susceptible to HIV-1 induced destruction. Our primary hypothesis is that the elimination of thymocytes by HIV- 1 occurs primarily by indirect perturbation of the normal processes of thymocyte growth and differentiation. The specific aims presented below outline an approach to the cellular and molecular analysis of this hypothesis. We are confident that the results of these studies will provide a more in depth knowledge of human thymocyte development, of the molecular and cellular mechanisms of HIV-1 pathology within the thymus, and of potential therapeutic regimens for augmenting the regenerative capacity of the immune system in both children and adults. AIM I:TO DETERMINE THE STAGES AT WHICH HIV-l CAN DISRUPT THYMOCYTE VIABILITY AND MATURATION AIM 2: TO DETERMINE THE MOLECULAR BASIS OF HIV-I INDUCED ThYMOCYTE APOPTOSIS AIM 3: TO DETERMINE WHETHER HIV-I INDUCES APOPTOSIS BY ALTERED ThYMOCYTE SIGNALING